DBDR Embraces Cross-Cutting Science: A Paradigm for the Future of Scientific Discovery

How do you define cross-cutting science, and how is this concept being incorporated into DBDR’s mandate?

Cross-cutting science (CCS) serves as a primary rationale for undertaking this reorganization. It is inextricably linked to the need for team science since no single scientist or lab can master all the nuances of multiorgan pathogenesis. Teams of diverse individuals or groups approaching a scientific question from alternative perspectives enable a more integrated investigation that may increase both the rate and the depth of discovery. Fostering these collaborations is essential to our responsibilities as a national research program charged with enabling blood science.

In the context of our reorganization, we define CCS in at least three ways: First, we define it in terms of science that falls in the “gray zone” between the three branches, requiring ongoing conversations between two or all three branches. To expedite this essential dialogue, we are creating project groups to develop new scientific initiatives that do not fall neatly or exclusively into our organizational niches. An example would be developing a pathway for a newly developed drug to progress from first-in-human safety studies to phase II efficacy studies, toward a pivotal licensure trial. At a minimum, members from TBSR and BECT would need to collaborate to chart the funding course forward.

A second definition of CCS includes the essential collaborations across NHLBI. These CCS efforts can be institutewide or bilateral efforts between DBDR and either the Division of Lung Diseases or the Division of Cardiovascular Sciences. With regard to the former, one recent success has been the development of a sickle cell disease (SCD) transinstitute collaborative: it will test strategies to improve the incorporation of proven therapies within the adolescent and adult SCD community. Other examples of bilateral work between divisions include the co-sponsoring of scientific initiatives in the pathophysiology of sepsis/pneumonia with our colleagues in NHLBI’s Lung Division and shared efforts with the Cardiovascular Sciences Division to promote research in vascular biology across the arterial-microvasculature-venous continuum.

A third and very important CCS strategy for us entails cross-institute (NIH) or cross-agency (e.g., the U.S. Department of Defense [DoD]) collaborations. Not only do such efforts often enable us to leverage shared funding for common research endeavors, but they often allow entities that are chartered to target research in diverse organ foci to collaborate to undertake essential research at interfaces between the organ-centric areas. One example we are pursuing is a collaboration with the National Institute of Neurological Disorders and Stroke (NINDS) to engender new research into the blood-brain barrier based on recent research showing the complex interplay between the cells and circulating proteins of the systemic circulation and their messaging to critical cells in the central nervous system. In addition, we work closely with our colleagues in the DoD to support research in the coagulopathy of trauma and its treatment.

Additional CCS enterprises that we are aggressively supporting focus on the molecular and cellular infrastructure that defines regenerative capacity in human injury states. Efforts to define this process entail CCS such as “organ on a chip,” induced pluripotent stem cell development, and propagation and cell-cell cross-talk. Organ-specific efforts are ongoing in multiple Institutes at NIH. Yet the inter-Institute collaborations being promoted by the National Center of Applied Sciences (NCATS) are playing an essential role in assuring that CCS scientific initiatives will benefit from an integrated effort at NIH.

What do you see as the potential impact of CCS on the next wave of discovery and progress within the hematologic community?

CCS will likely expand and expedite scientific discovery. Through CCS and the team science that goes with it, scientific discoveries in one area can more quickly catalyze discovery in another area. Without CCS and team-based science, such beneficial connections between areas of expertise might take years to happen, if they happen at all. By hematologists working with infectious disease experts, for example, more may be learned and faster about blood-borne parasitic infections such as malaria, and particularly, emerging blood-borne pathogens.

In addition to the intergovernmental collaborations noted above, progress within the hematologic community will depend on creative public-private partnerships dedicated to CCS. For example, with the National Cancer Center, we are creating a myelodysplastic syndrome (MDS) resource that will permit longitudinal assessment of genomic and epigenomic/transcriptomic changes within hematopoetic progenitor cells in a cohort of patients with MDS as compared with a contemporaneous cohort of age-matched individuals with unexplained anemia/thrombocytopenia (e.g., idiopathic cytopenias of underdetermined significance [ICUS]). We hope that this will provide molecular insight into what drives MDS and its not-invariable progression to acute myeloid leukemia.

The future of CCS will be dependent on how well we cultivate the future research workforce. Although federal funding that has not kept pace with inflation has certainly helped to create this challenge, there is a consensus that money alone will not solve the problem. Attention to every aspect along the educational continuum, including enhancing resources, will be required: From early STEM education in primary and secondary schools to shortening of the research career trajectory to support of mid-career MDs, MD-PhDs, and PhDs. Enhancing all of these educational areas and the development of many other creative strategies are needed to meet this challenge. DBDR is committed to collaborating with all partners to address this most critical of challenges.

How does the reorganization affect funding opportunities and priorities within the NHLBI?

The reorganization of DBDR is revenue neutral for DBDR and NHLBI. It will not affect the funding of investigator-initiated research applications (e.g., R01s, P01s, etc.). It also will not affect the total funding available for requests for applications (RFAs), requests for proposals, or program announcements with review —referred to as initiatives. Nonetheless, since DBDR proposals compete for initiative monies based on scientific rationale and meeting a scientific need or filling a scientific gap, it is our hope that our new integrated approach will foster more enhanced initiative proposals that will fare well within the institute.

Given the ASH Agenda for Hematology Research and DBDR’s restructuring, how do you see our professional organization and your agency working together to synergize efforts?

The 2015 ASH Agenda for Hematology Research identified six areas of priority for research support (including dedicated resources from funding agencies): 1) genomic profiling and chemical biology, 2) immunologic treatments of hematologic malignancies, 3) genome editing and gene therapy, 4) stem cell biology and regenerative medicine, 5) epigenetic mechanisms, and 6) venous thromboembolic disease.

Aside from the second priority focused on hematologic malignancies and immunotherapy (more appropriately the province of the National Cancer Institute), DBDR shares theses priorities. As I have discussed above, for example, regenerative medicine and stem cell biology are a focus of both ongoing research support as well as our cross-cutting emphases for future scientific emphasis. We are presently supporting such efforts both through investigator-initiated research project grants as well as targeted initiatives such as the RFA for basic stem cell biologic approaches to blood “pharming” (R01) and the technological applied research to support this effort (e.g,, through the Small Business Innovation Research [SBIR] and Small Business Technology Transfer [STTR] programs).

With regard to genomic profiling, we are presently participating in the NHLBI TOPMED (Trans-Omics for Precision Medicine) program, which is underwriting whole genome sequencing for existing NHLBI cohorts. For DBDR, this translates to a commitment to sequence DNA from patient cohorts with SCD, hemophilia, platelet disorders, and venous thromboembolism (VTE). (SCD was an ASH priority for 2014.) All of the hematologic cohorts to undergo DNA sequencing will have extensive phenotyping performed longitudinally over several years. This will permit a careful scrutiny of yet-to-be characterized genes of influence in the monogenic diseases such as SCD and will allow an exonic and intronic examination of the “acquired” polygenic diseases such as VTE. Furthermore, in relation to the ASH priority of deciphering epigenetic mechanisms, the long-term strategy for TOPMED is to supplement the whole genome sequencing with targeted epigenetic sequencing. Ultimately, these efforts should provide an important foundation for precision medicine for patients with both common and rare hematologic diseases.

Gene transfer has been a mainstay of DBDR translational research efforts for nearly two decades. We have provided vector production support for multiple phase I trials on hemophilia B, for example. More recently, investigators we support by both R01 grants and targeted RFAs are doing seminal work in gene editing for SCD and severe combined immune deficiencies. We have supported work utilizing editing strategies for zinc-finger nucleases and the TALENS and CRISPR-Cas9 enzymes for SCD and thalassemia. Under the reorganization, the TBSR Branch is developing a long-term strategy for scientific and resource support for advanced gene transfer and gene editing to move toward a cure for multiple monogenic hematologic diseases.

Finally, with regard to VTE, DBDR is exploring with our colleagues in National Cancer Institute (NCI) strategies to understand more extensively how cancer predisposes patients to pathogenic clotting — a collaborative approach that will likely engage all three of our new Branches. We think that combining the oncologic expertise of investigators funded by NCI and the cohorts they have assembled with the basic, translational, and clinical coagulation expertise of DBDR-funded thrombosis investigators offers unique opportunities to extend our knowledge in this important clinical area.

Which of DBDR’s accomplishments are you most proud of during your tenure there and what is an example of a concrete endpoint you’d like to see DBDR achieve with the reorganization?

I am most proud of the team that we have assembled to accomplish the DBDR reorganization. It consists of some very experienced and dedicated scientists who have shepherded hematologic research over several decades and some newer arrivals who have brought new enthusiasm and new expertise that will enable DBDR to pursue the long-term goals discussed above. I am particularly indebted to the DBDR Deputy Donna DiMichele and the Branch Chiefs of the reorganized Branches (the DBDR Leadership Team) who have helped to engineer the process and spread the word across the “Heme” community about the how, why, and when of the reorganization. Already, we are seeing both new avenues of science (for DBDR) being pursued and broad resources being leveraged to enhance capacity.

We are very proud of the new SCD initiative for implementation science and the successful collaboration of DBDR with DoD and the NHLBI Division of Cardiovascular Sciences to complete the “PROPPR” (Pragmatic Randomized Optimal Platelet and Plasma Ratios) trial of transfusion components for severe trauma. We are also proud of the DoD-DBDR Trans-Agency Collaboration in Trauma-Induced Coagulopathy (TACTIC), the substantial translational initiatives in both hemoglobinopathies and hemostasis/thrombosis, and the other programs cited above. Additionally, we are proud of the work we have done to enhance opportunities for the next generation of researchers in blood science and are determined to enhance efforts in this area.

A particularly important example of what would constitute a concrete endpoint for us is to increase the number of investigators nationally who research blood science. Achieving this will require close work with many other stakeholders including ASH. We must turn the curve on the declining research workforce in blood science. Multiple strategies across many organizations and agencies will be required. The pursuit of great science is, we believe, worth the effort.